tbuckley/cabot-search huggingface dataset:
Nivolumab (NIVO) ± ipilimumab (IPI) in patients (pts) with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): Five-year follow-up from CheckMate 142.
Authors: Michael J. Overman, Heinz-Josef Lenz, Thierry Andre, Massimo Aglietta, Mark Ka Wong, Gabriele Luppi, Eric Van Cutsem, Raymond S. McDermott, Alain Hendlisz, Dana Backlund Cardin, Michael Morse, Bart Neyns, Andrew Graham Hill, M. Luisa Limon, Pilar Garcia-Alfonso, Anuradha Krishnamurthy, Franklin Chen, Sandzhar Abdullaev, Samira Soleymani, Sara Lonardi
Journal: Journal of Clinical Oncology (2022)

3510 Background: NIVO ± IPI is approved in previously treated pts with MSI-H/dMMR mCRC in the US, EU, and Japan, based on findings from the phase 2 CheckMate 142 study (NCT02060188). NCCN guidelines include NIVO + IPI as an initial therapy option for pts with MSI-H/dMMR mCRC. Results from a ~5-year follow-up from CheckMate 142 cohorts 1–3 (C1–3) are reported here. Methods: In this non-randomized, multicohort study, pts with MSI-H/dMMR mCRC were treated as follows: C1 (2L+; NIVO 3 mg/kg Q2W), C2 (2L+; NIVO 3 mg/kg + IPI 1 mg/kg Q3W [4 doses], followed by NIVO 3 mg/kg Q2W) and C3 (1L; NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W), until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by investigator assessment (INV) per RECIST v1.1. Other key endpoints were disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), all by INV and blinded independent central review; overall survival (OS), and safety. Results: In C1 (N = 74), C2 (N = 119), and C3 (N = 45), median (range) follow-up (time from first dose to data cutoff) was 70.0 (66.2–88.7), 64.0 (60.0–75.8), and 52.4 (47.6–57.1) months (mo), respectively. ORR (95% CI) by INV was 39% (28–51), 65% (55–73), and 71% (56–84; Table) and progressive disease (PD) rates were 26%, 12%, and 16% in C1, C2, and C3, respectively. Median DOR was not reached in the 3 cohorts. The 48-mo PFS rates were 36%, 54%, and 51% and 48-mo OS rates were 49%, 71%, and 72% in C1, C2, and C3, respectively (Table). PFS and OS rates with up to 60 mo of follow-up will be presented. Safety data are shown in the table. Conclusions: With extended follow-up of ~5 years, NIVO ± IPI continued to demonstrate durable OS and PFS benefit, with no new safety signals. These updated data further support current treatment recommendations for 2L+ NIVO ± IPI and 1L NIVO + IPI for pts with MSI-H/dMMR mCRC. Clinical trial information: NCT02060188. [Table: see text]
Medicare expenditures for discarded oncology therapies.
Authors: Caleb Scheckel, Aakash Desai, Chelsee Jensen, Jacob Orme, Joshua Pritchett, Amit Mahipal, Nandita Khera, Ronald S. Go
Journal: Journal of Clinical Oncology (2022)

6552 Background: Significant amounts of expensive oncology drugs are discarded resulting in waste and financial consequences for patients. Beginning in 2023, the Infrastructure Investment and Jobs Act (IIJA) will require drug manufacturers to refund Medicare for any single-use drugs where greater than 10% of the drug is wasted. We explored potential IIJA-associated savings through assessment of patterns in spending for discarded oncology agents between 2017-2020. Methods: We utilized the Medicare Part B Discarded Drug Units database from 2017-2020. Using J codes, we extracted spending and reimbursement data for discarded medications for antineoplastic and classical hematology therapies. The primary outcome was identification of therapies with high percentage of waste and the economic impact of retroactive application of the IIJA for discarded therapies. Results: Medicare Part B utilization data was extracted for a median 77 (64-152) oncologic therapies per year with median reimbursement for discarded treatments of $590 M ($566-616). From 2017-2020, bortezomib, romiplostim, and nab-paclitaxel were consistently among the top 5 therapies by value of wasted product. Pembrolizumab waste by value declined significantly after 2017 following transition to fixed dosing. In 2020, the top 5 therapies by value of wasted product were bortezomib, nab-paclitaxel, trastuzumab, romiplostim, and cabazitaxel with a value of $278 M. In 2020, the agents with the highest percentage of wasted product were bortezomib (27%), cabazitaxel (28%), decitabine (23%), topotecan (23%), and azacitidine (22%) with a collective discarded value of $160 M. Notably, these agents have weight-based dosing and single-use vials. Based upon the average number of drug claims per recipient and volume of product discarded, eliminating drug waste would allow an additional 6564 patients to receive treatment with discarded bortezomib. The number of additionally treated patients for the other top 5 agents: cabazitaxel (1216), decitabine (1509), topotecan (291), and azacitidine (2682). Retroactive application of IIJA policy would have impacted a median 20 (12-26) oncology agents resulting in median annual cost savings of $153 M (142-157) and the median annual spending on wasted oncology therapies would decline to $440 M (410-466). Conclusions: The IIJA would have yielded a median annual savings of $153 M in Medicare spending if applied retroactively. Given a 10% waste cutoff, a limited number of agents would be targeted by this legislation. In our study, we observe that drugs associated with weight-based dosing and single-use drug vials account for most drug waste. Strategies to minimize discarded units (through storage of unused product, approval of multi-dose vial formulations, or fixed-dose therapies) could yield substantial savings while enabling health equity in collaboration with communities with difficult access to these drugs.
Breast cancer incidence in patients with <i>BRCA</i>-related advanced ovarian cancer receiving olaparib-based maintenance therapy: A pooled analysis from phase III clinical trials.
Authors: Michele Bartoletti, Marcella Montico, Roberta Mazzeo, Marco De Scordilli, Lucia Musacchio, Emilio Lucia, Giorgio Giorda, Samuele Massarut, Martina Urbani, Gianmaria Miolo, Alessandra Viel, Mattia Garutti, Lucia Da Ros, Simona Scalone, Milena Nicoloso, Serena Corsetti, Roberto Sorio, Domenica Lorusso, Sandro Pignata, Fabio Puglisi
Journal: Journal of Clinical Oncology (2022)

5566 Background: As the prognosis of BRCA-related advanced ovarian cancer (AOC) continues to improve thanks to the introduction of targeted therapies like poly ADP-ribose polymerase inhibitors (PARPi) and bevacizumab, the occurrence of second primary tumors, in particular breast cancer (BC), is assumed to be more common. Despite this, data on the incidence of BC in this population are poor and guidelines for BC screening or risk reducing strategies are lacking. Methods: Published data from recent PARPi-based, phase III clinical trials involving germline BRCA mutated AOC were reviewed and analyzed. Only studies in which the incidence of at least one second primary solid tumor was reported were included. Cases of second primary BC cancers were pooled to calculate cumulative incidence according to the median follow-up period for each trial. 95% confidence interval (CI) was considered. Results: Four trials (SOLO1, PAOLA1, SOLO2 and SOLO3) involving 1186 germline BRCA 1-2 mutated AOC patients were included ( BRCA1, n = 816; BRCA2, n = 360; BRCA1 + BRCA2, n = 4; missing, n = 6). In all trials, patients were randomized to receive olaparib +/- bevacizumab (n = 788) versus placebo or standard therapies (n = 398). Median age at diagnosis of AOC was 56 years (range, 29-87). With a follow-up ranging from 3.9 months to 5 years, 16 new cases of BC were recorded, 10 in PARPi-based arms and 6 in control arms. Only two patients had a previous history of BC. The total cumulative incidence of BC was 1.37% (95% CI, 0.77-2.18), while cumulative incidences were 1.26% (95% CI, 0.61-2.31) and 1.51% (95% CI, 0.55-3.25) in PARPi-based arms and control arms, respectively. In a sensitivity analysis excluding the SOLO3 trial with the shortest follow-up, the total cumulative incidence was 1.63% (95% CI, 0.92-2.67). Other 20 cases of second primary solid tumors were registered, including 4 cases of non-small cell lung cancer. Conclusions: Patients with germline BRCA-related AOC receiving PARPi-based maintenance therapy can be reassured about the risk of second primary BC and intensive screening should be avoided at least in early treatment phase. More data with long term follow-up are needed.
Glycoproteomics as a powerful liquid biopsy-based screening tool for non-small cell lung cancer.
Authors: Alan Mitchell, Chad Pickering, Gege Xu, Rachel Rice, Alyn Castellanos, Ranjan Bhadra, Luka Brcic, Joerg Lindenmann, Freyja Smolle, Klaus Lindpaintner, Danie Serie
Journal: Journal of Clinical Oncology (2022)

e21148 Background: Protein glycosylation is the most abundant and complex form of post-translational protein modification. Glycosylation profoundly affects protein structure, conformation, and function. The elucidation of the potential role of differential protein glycosylation as biomarkers has so far been limited by the technical complexity of generating and interpreting this information. We have recently established a novel, powerful platform that combines liquid chromatography/mass spectrometry with a proprietary artificial-intelligence-based data processing engine that allows, for the first time, highly scalable interrogation of the glycoproteome. Methods: Using this platform, we interrogated 694 glycopeptide (GP) and non-glycosylated peptide transitions derived from 74 serum proteins in pre-treatment peripheral blood samples from a cohort of 316 individuals with non-small-cell lung cancer (NSCLC) (128 females, 187 males, 1 with unknown sex, median age 66 years, age range 31-89 years, stage 0-4 N’s: 1 / 99 / 80 / 84 / 49, 3 missing) and a comparison cohort of 194 healthy control samples (102 females, 92 males, median age 52 years, age range 30-63 years). Age- and sex-adjusted differential expression analysis for 596 normalized biomarkers were performed to evaluate statistically significant differential abundances using an FDR-adjusted q-value of 0.05 as a cutoff. Repeated five-fold cross-validated LASSO-regularized logistic regression was performed to create a multivariable classifier that predicts whether a serum sample belongs to the healthy or NSCLC cohort. Results: We identified 432 biomarkers with significant abundance differences at FDR ≤ 0.05 between samples with NSCLC and healthy controls. Using 70% of the complete cohort (balanced by case/control membership, NSCLC stage, sex, and age quartile) as a training set, we selected a total of 375 glycopeptide and non-glycosylated peptide biomarker features that remained differentially expressed at FDR-adjusted q-value ≤ 0.05 as input into a LASSO-regularized multivariable classifier. This resulting in a 19-biomarker model exhibiting an accuracy of 94.8% (96.9% sensitivity, 91.2% specificity) and AUC of 0.989. This classifier was validated in an independent test set comprising the remaining 30% of subjects, yielding an accuracy of 94.5% (95.5% sensitivity, 93.0% specificity) and AUC of 0.975. Sensitivity in the test set was 100% / 96% / 99% / 96% / 94% / 10%, in stages 0-4 and missing, respectively. Conclusions: Our results indicate that glycoproteomic biomarkers can be leveraged as a strong liquid biopsy-based screening tool for patients at high risk of NSCLC, as an alternative to imaging modalities.
Assessment of FOXC1 expression as a predictor of response to neoadjuvant taxane plus platinum regimens in primary triple-negative breast cancer: Retrospective analysis of three clinical trial cohorts.
Authors: Partha Ray, Tania Ray, Sara Lopez-Tarruella Cobo, Maria del Monte Millan, Enrique Álvarez, Yolanda Jerez Gilarranz, Marta Roche, Clive R. Taylor, Miguel Martin
Journal: Journal of Clinical Oncology (2022)

569 Background: Taxane and platinum (TP) NAC regimens, e.g. Carboplatin and Docetaxel (CbD), in TNBC are currently of great interest, having good pathologic complete response (pCR) rates but with a significantly more manageable toxicity profile compared to anthracycline-based NAC regimens. Forkhead Box C1 (FOXC1), a transcriptional driver of cell plasticity/partial EMT/metastasis is an established mesenchymal marker diagnostic of basal-like breast cancer having proven prognostic value, but of uncertain predictive value. We sought to evaluate the potential of FOXC1 in predicting pCR to neoadjuvant TP regimens in patients diagnosed with TNBC. Methods: Pre-NAC tumor biopsy FOXC1 mRNA expression status was correlated with rate of pCR in a pooled, ambispective cohort (prospective cohort GEICAM/2006-03, NCT00432172 pooled with multi-institutional retrospective cohort, n = 119). A specific FOXC1 mRNA expression cutoff value was derived to maximize Negative Predictive Value (NPV) and Sensitivity for pCR prediction. The pCR-predictive ability of FOXC1 mRNA expression was then assessed in two validation cohorts of evaluable patients who had been enrolled in prospective clinical trials (UCONN/FIOCRUZ, n = 222, HGUGM, NCT01560663, n = 221). All evaluated patients had been diagnosed with TNBC and had received a Taxane plus Platinum-based NAC regimen. Results: FOXC1 mRNA expression was associated with pCR in CbD/TP treated TNBC patients with pCR rates of 43.48%, 47.89% and 52.73% observed in the discovery and two validation cohorts (two tailed T-test p-values of 0.0005, 0.002, 0.009, respectively). FOXC1 expression above the pre-determined cutoff value was associated with pCR to CbD/TP NAC in patients diagnosed with TNBC in both validation cohorts (OR 4.894, 1.504-15.924; p = 0.004 and OR 2.293, 1.208-4.352; p = 0.006). Conclusions: We report the retrospective validation of pre-NAC breast cancer biopsy FOXC1 mRNA expression for predicting efficacy of CbD/TP NAC in two independent, prospectively accrued TNBC patient cohorts. The described strategy may be acceptable for patient stratification to guide CbD/TP NAC recommendations in TNBC. FOXC1 mRNA or protein expression, assessed using qRT-PCR or routine immunohistochemistry (IHC), respectively, could potentially be utilized in future fixed-arm/adaptive clinical trials to further optimize NAC efficacy, in terms of achieved pCR rates, and to extend disease-free survival in patients diagnosed with TNBC.
Anlotinib combined with nab-paclitaxel and cisplatin as neoadjuvant treatment for esophageal squamous cell carcinoma (ESCC): A single-arm, open-label phase II clinical trial.
Authors: Yan-Feng Zhang, An-Lin Hao, Yong-Gui Hong, Xiao-Ming Li, Wei-Min Liang, Zhi-Xin Zheng, Guang-Yi Yang, Xiao-Feng Guo, Yan-Yan Wen, Heng Cao, Cheng Le, Hua-Jie Song, Wen-Zhong Su
Journal: Journal of Clinical Oncology (2022)

e16015 Background: Neoadjuvant therapy could significantly improve survival for patients with locally advanced esophageal cancer. However, postoperative complications and recurrence are still urgent problems to be solved. Anlotinib was an effective second-line monotherapy for ESCC in China and the combination therapy might be a promising strategy. Nab-paclitaxel plus cisplatin as first-line therapy exhibited moderate efficacy in ESCC patients. This study was to investigate the efficacy and safety of nab-paclitaxel and cisplatin combined with anlotinib as neoadjuvant treatment for ESCC. Methods: ESCC patients with preoperative clinical stage II-III and all patients who can receive radical surgery were recruited in this study. Eligible patients received anlotinib (12mg, po, d1̃14, q3w) combined with nab-paclitaxel (175mg/m 2 , iv, q3w) and cisplatin (20mg/m 2 , iv, d1̃3, q3w) for 2 cycles during neoadjuvant therapy. 4 weeks after the end of neoadjuvant therapy, the patients underwent radical surgery after exclusion of contraindications to surgery. Tumor response was assessed by investigator according to RECIST version 1.1 using CT scans at baseline and within 2 weeks before surgery. The calculated sample size was 62. The primary endpoint was ORR, secondary endpoints were R0 resection rate, DFS, OS, DCR and safety. Results: From Apr 2021 to Dec 2021, a total of 26 eligible patients were enrolled. Among them, 17 patients underwent surgery after completing 2 cycles of neoadjuvant therapy, 3 patients chose other treatment options, and 6 patients are still receiving neoadjuvant therapy. patients who had received surgery (n = 17) were included in this analysis. In best overall response assessment, there were 4 CR (23.5%), 11 PR (64.7%) and 2 SD (11.8%). Consequently, ORR was 88.2% (95%CI: 63.6̃98.5%) and DCR was 100.0% (95%CI: 80.5̃100.0%). At the data cut-off date, 17 patients (100.0%) had underwent R0 resection. Among them, 4 patients (23.5%) were confirmed to be pCR. And the median DFS was not yet available. The safety profile suggested that the most common treatment-emergent adverse events with the incidence &gt; 10% were gastrointestinal reactions (65.4%), hypokalemia (19.2%), nausea (15.4%), liver damage (15.4%), myelosuppression (11.5%) and vomit (11.5%). No grade ≥3 adverse events were noted. Conclusions: Preliminary results suggested that anlotinib combined with nab-paclitaxel and cisplatin in neoadjuvant treatment of ESCC exhibited encouraging efficacy and manageable adverse events. The conclusion should be validated in more patients included subsequently.
Combination of immune checkpoint inhibitors plus chemotherapy and risk of pneumonitis: A worldwide retrospective pharmacovigilance study.
Authors: Yi-Fan Zheng, Pei-Hang Xu, Zi-mu Li, Yu-Kun Kuang, Jia Li, Jun-Hao He, Xiao Chen, Ke-Jing Tang
Journal: Journal of Clinical Oncology (2022)

e14587 Background: Pneumonitis is one of the most common fatal pulmonary adverse events that stem from immune checkpoint inhibitors (ICIs). Although the combination of ICI plus chemotherapy has become the standard first-line treatment regiments for various tumors, how the risk of pneumonitis changes during the combination treatments remains unclear. We used the World Health Organization pharmacovigilance database (VigiBase) to compare the risk of pneumonitis from the combinations of ICI plus chemotherapy with ICI in other regimens, including monotherapy. Methods: This observational, retrospective, pharmacovigilance study is a disproportionality analysis based on the individual case safety reports (ICSRs) extracted from the VigiBase from 1997 to 2020. The disproportionality analysis (known as case-non-case analysis) was conducted to compare the reporting of pneumonitis from the combination of ICI plus chemotherapy with ICI in other drug regimens, including monotherapy. The reporting odds ratio (ROR) and 95% confidence interval (CI) were calculated. Results: From 1994 to 2020, A total of 93,623 ICI-associated ICSRs were reported in Vigibase, including 3,453 reports of pneumonitis (3.7%), among which 274 were associated with the combinations of ICI plus chemotherapy. The median time to event onset occurred about 2 months after therapy either in ICI without chemotherapy group or in the combination with chemotherapy group (61.5 days vs 74 days, respectively, p &gt; 0.05). The ICI plus chemotherapy combination demonstrated a significant association with pneumonitis (ROR 1.35, 95% Cl 1.18-1.52). Among all the ICIs, anti-PD-1 antibodies combinations and anti-CTLA-4 antibodies combinations demonstrated a significant association with pneumonitis (PD-1+chemotherapy: 1.76, 95 % CI 1.52-2.05; CTLA-4+chemotherapy: 2.36, 95% Cl 1.67-3.35), while anti-PD-L1 antibodies plus chemotherapy combinations did not show similar association (ROR 0.37, 95% Cl 0.28-0.47). Conclusions: The combination of ICI plus chemotherapy is associated with higher risk of pneumonitis toxicity compared to other ICI-containing regimens (including ICI monotherapy) based on real-world data. The anti-PD-L1 plus chemotherapy combination has different pneumonitis profiles compared to anti-PD-1/CTLA-4 combinations. It suggests that a close monitoring for pneumonitis may be needed when using ICI plus chemotherapy combinations.[Table: see text]
Anlotinib plus tislelizumab combined with chemotherapy as neoadjuvant treatment in triple-negative breast cancer: A prospective, single-arm, open-label phase II study.
Authors: Jing Luo
Journal: Journal of Clinical Oncology (2022)

TPS618 Background: Neoadjuvant anti-PD-(L)1 therapy confers an improvement in pathological complete response (pCR) rate in unselected triple-negative breast cancer (TNBC). Combination of antiangiogenic agent plus immune checkpoint inhibitor and chemotherapy therapy for advanced TNBC is reported as a promising anti-tumor strategy presented in the FUTURE-C-PLUS study. Tislelizumab is a humanized immunoglobulin G4 anti-PD-1 monoclonal antibody engineered to minimize binding to FcγR on macrophages. Anlotinib is a novel multi-target tyrosine kinase inhibitor that effectively inhibit VEGFR, FGFR, c-KIT, c-MET and RET. Previous studies have proven the efficacy of both anlotinib monotherapy and combination with immune checkpoint inhibitor in advanced breast cancer. This phase II study aims to evaluate the efficacy and safety of anlotinib plus tislelizumab combined with chemotherapy as neoadjuvant treatment in TNBC. Methods: This is a prospective, single-arm, open-label, phase II trial. Eligible patients (pts) were women, aged 18-75 years, ECOG status 0-1, previously untreated invasive TNBC with histologically confirmed (cT1N1-2M0 or cT2-4N0-2M0). 32 pts will be enrolled and received 5 cycles of anlotinib (8 mg qd, d1-14; 21 days per cycle) with 6 cycles of tislelizumab (200 mg, once every 3 weeks) plus nab-paclitaxel (260 mg/m 2 , once every 3 weeks) and anthracycline (epirubicin 75 mg/m 2 or doxorubicin 60 mg/m 2 ), followed by surgery. The primary endpoint is pathological complete response rate (pCR, ypT0/Tis ypN0) and the secondary endpoints include invasive disease-free survival (iDFS), event-free survival (EFS), overall survival (OS), and safety. A sample size of 32 patients was estimated to provide a 80% power to detect a difference of 25% in pCR at a significance level of α = 0.05. The study was initiated in August 2021. Clinical trial information: NCT04914390.